Phenyl alkyl carbamate compounds for use in preventing or treating neurodegenerative disease
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Publication Number
US-11931332-B2
Publication Date
2024-03-19
Expiration Date
Abstract
The present invention relates to a phenyl alkyl carbamate compound for use in preventing or treating neurodegenerative diseases. The phenyl alkyl carbamate compound of the present invention, prevented dopaminergic neuron loss, attenuated activation of astrocyte/microglia, repressed phosphorylated alpha-synuclein, and regulated phosphorylation levels of tau and acetylation levels of alpha-tubulin in the Parkinson's disease animal model. In addition, the phenyl alkyl carbamate compound of the present invention reduced the Amyloid-beta precursor protein and Amyloid-beta. Therefore, the phenyl alkyl carbamate compound of the present invention may be effectively used for preventing or treating neurodegenerative diseases.
Core Innovation
The invention relates to phenyl alkyl carbamate compounds represented by formula 1, including pharmaceutically acceptable salts, and their use as active ingredients for treating neurological diseases. The compounds are defined by substituent variables including X as a halogen with n from 1 to 5, R1 as hydrogen or a linear or branched C1-C4 alkyl group, and A and B as allyl, a C1-C19 linear or branched alkyl group, a C2-C8 alkoxy alkyl ether group, or a carbamoyl derivative.
The structural variables further include R2 and R3, which may be the same as or different from each other and are independently selected from hydrogen, a linear or branched C1-C4 alkyl group, a C3-C8 cycloalkyl group, and benzyl group. The disclosed examples include halogenated phenyl alkyl carbamate analogs with 2-chlorophenyl, 2-fluorophenyl, 2-iodophenyl, and 2,3-/2,4-/2,6-dichlorophenyl variants, together with stereoisomeric forms such as (S,S), (R,R), (S), and (R).
The invention is presented in connection with treatment methods for Parkinson’s disease or Alzheimer’s disease, dopamine neuron loss or a disease caused by dopamine neuron loss, activation of astrocytes and glial or neurotoxicity occurred by immune process, α-synucleinopathy or a disease associated with the presence of α-synuclein aggregates, and diseases associated with overexpression of amyloid-beta precursor protein or amyloid-beta. The compounds are administered to a subject in need thereof in a pharmaceutically effective amount as a phenyl alkyl carbamate compound or a pharmaceutically acceptable salt thereof.
Claims Coverage
Five independent method claims are provided. Across the claims, the inventive features are administration of a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1, or a pharmaceutically acceptable salt, using the same structural-variable framework for X, n, R1, A, B, and independently selected R2 and R3. The claims differ by the specified therapeutic target.
Parkinson’s disease or Alzheimer’s disease treatment with formula 1 phenyl alkyl carbamate
Administering, to a subject in need thereof, a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein X is a halogen; n is an integer from 1 to 5 with X being the same or different each other when n is 2 or larger; R1 is hydrogen or a linear or branched C1-C4 alkyl group; A and B are selected from allyl, a C1-C19 linear or branched alkyl group, a C2-C8 alkoxy alky ether group, or a carbamoyl derivative; and R2 and R3 are independently selected from hydrogen, a linear or branched alkyl group of C1-C4, a cycloalkyl group of C3-C8, and benzyl group.
Dopamine neuron loss treatment with formula 1 phenyl alkyl carbamate
Administering a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1 or a pharmaceutically acceptable salt thereof to treat dopamine neurons loss or a disease caused by dopamine neurons loss, with the same structural-variable framework for X, n, R1, A, B, and independently selected R2 and R3.
Astrocytes and glial activation or immune-process neurotoxicity alleviation with formula 1 phenyl alkyl carbamate
Administering a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1 or a pharmaceutically acceptable salt thereof to alleviate an activation of astrocytes and glial, or to alleviate a neurotoxicity occurred by immune process, with the same structural-variable framework for X, n, R1, A, B, and independently selected R2 and R3.
α-synucleinopathy treatment with formula 1 phenyl alkyl carbamate
Administering a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1 or a pharmaceutically acceptable salt thereof to treat α-synucleinopathy or a disease associated with the presence of α-synuclein aggregates, with the same structural-variable framework for X, n, R1, A, B, and independently selected R2 and R3.
Amyloid-beta precursor protein or amyloid-beta overexpression-associated disease treatment with formula 1 phenyl alkyl carbamate
Administering a pharmaceutically effective amount of a phenyl alkyl carbamate compound represented by formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with overexpression of amyloid-beta precursor protein or amyloid-beta, with the same structural-variable framework for X, n, R1, A, B, and independently selected R2 and R3.
The claims consistently cover administering a formula 1 phenyl alkyl carbamate compound, or a pharmaceutically acceptable salt, defined by halogen substitution X and n, R1, A, B, and independently selected R2/R3 groups. The inventive coverage is differentiated by the disease or condition addressed in each independent claim.
Stated Advantages
Prevention of dopaminergic neuron loss.
Attenuation of astrocyte activation.
Attenuation of microglia activation.
Repression of phosphorylated α-synuclein (p-α-syn).
Modulation of tau phosphorylation (p-Tau s262).
Modulation of α-tubulin acetylation (Ace-α-tubulin).
Reduction of APP and amyloid-beta (Aβ).
Documented Applications
Preventing or treating neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.
Treating dopamine neuron loss or a disease caused by dopamine neuron loss.
Alleviating activation of astrocytes and glial, or alleviating neurotoxicity occurred by immune process.
Treating α-synucleinopathy or a disease associated with the presence of α-synuclein aggregates.
Treating a disease associated with overexpression of amyloid-beta precursor protein or amyloid-beta.
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